: Respiratory failure from the acute respiratory distress syndrome (ARDS) ac- counts for 4 million ICU days annually in the U.S., placing a significant burden on public health resources. Lung-protective ventilation relies on positive end-expiratory pressure (PEEP) to limit end-expiratory derecruit- ment, and low tidal volumes to reduce inspiratory overdistention. While such ventilatory strategies have signif- icantly improved outcomes in ARDS, mortality nonetheless remains high. Since ventilation distribution in ARDS is governed by a heterogeneous distribution of regional mechanics, the most appropriate distending pressure, ventilation frequency, or tidal volume for one lung region may not necessarily be the same for anoth- er, even in the same patient. This may result in substantial regions of the lung being under- or over-ventilated, with poor ventilation-to-perfusion matching and increased dead space. Recently, we demonstrated that lung function and gas exchange can be significantly improved in heterogeneous preterm lungs if volume oscillations are applied at multiple simultaneous frequencies, rather than at a single discrete frequency (Kaczka et al. An- esthesiology 123:1394-1403, 2015). We termed this unique modality of mechanical ventilation as ?Multi- Frequency Oscillatory Ventilation? (MFOV), and proposed that such improved physiologic outcomes arose from the more even distribution of ventilation to different lung regions, in accordance with local mechanical proper- ties. However, the ability to generate high-fidelity MFOV waveforms in large-animal test subjects or adult hu- man patients is severely limited by existing ventilator technology. Experimental systems currently used for generating oscillations are not capable of providing high-amplitude flows or maintaining the respiratory system at a constant mean pressure during excitation. Thus, the OscillaVent R&D team's overall goal for this Phase I STTR application is to establish the feasibility of developing a commercially viable hybrid ventilator/oscillator capable of generating MFOV waveforms for use in adult human ARDS patients, as well as in large animals (as research subjects). The envisioned device will also be capable of generating conventional ventilator wave- forms. In Aim 1 we propose to develop a prototype ventilator/oscillator capable of generating flows, tidal vol- umes, and airway pressures at frequencies over ranges typically used for adult human conventional ventilation and oscillation, as well as MFOV. In Aim 2 we will demonstrate that our prototype ventilator/oscillator -- and MFOV in particular -- is capable of maintaining gas exchange in a large animal under baseline conditions and during heterogeneous lung injury. Based on our team's decades of expertise and strong preliminary data, the results obtained from this Phase I STTR project will have a high likelihood of establishing the foundation for a device capable of a new, viable mode of oscillatory ventilation in a broad range of respiratory failure patients. Phase I success will set the stage for the larger Phase II demonstration project that will provide the validation data needed to engage investors and/or licensing partners for STTR Phase IIB/Phase III commercialization.